This application claims the priority benefit under 35 U.S.C. xc2xa7 119(e) of U.S. Provisional Application No. 60/413,254, filed Sep. 25, 2002, the entirety of which is incorporated by reference herein.
1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to novel N-substituted hydromorphones.
2. Related Art
The primary location of pain control is in the central nervous system (CNS). The three primary classes of opioid receptors, xcexc (mu), xcexa (kappa), and xcex4 (delta), are distributed throughout the CNS and the periphery (Foss, J. F., The American Journal of Surgery 182 (Suppl to November 2001):19S-26S (2001)). xcexc, xcexa, and xcex4 opioid receptors are functionally coupled to pertussis toxin sensitive heterotrimeric G proteins (Gi) to inhibit adenylyl cyclase activity. Activation of these receptors activates K+ currents which increases K+ efflux, i.e., hyperpolarization, thereby reducing voltage-gated Ca2+ entry. Hyperpolarization of membrane potential by K+ currents and inhibition of the Ca2+ influx prevents neurotransmitter release and pain transmission in varying neuronal pathways. However, the principal receptor involved in pain management is the xcexc opioid receptor (Foss, J. F., ibid). Other consequences of xcexc-receptor activation include delays in gastrointestinal transit, respiratory depression, miosis, and feelings of well-being (euphoria) (Foss, J. F., ibid).
Opioids, also known as opioid agonists, are a group of drugs that exhibit opium or morphine-like properties, suppress neuronal activity at the above mentioned opioid receptors. The opioids are widely administered for a variety of medical indications but primarily they are employed as moderate to strong analgesics. Opioid compounds have been reported to have a number of side effects, including constipation, dysphoria, respiratory depresession, dizziness, nausea, and pruritus (Yuan, C.-S. et al., J. Pharm. Exp. Ther. 300:118-123 (2002)). CNS-mediated side effects include the abuse potential of opioids. Opioids are also effective as a preanesthetic medication and a cough suppressant, and in treating dyspnea, diarrhea and dysentery.
There have been attempts to selectively antagonize opioid-induced side effects via the use of receptor antagonists such as naloxone or nalmephene. However, the success has been limited because these compounds also reverse analgesia and induce opioid withdrawal (Yuan, C.-S. et al., J. Pharm. Exp. Ther. 300:118-123 (2002)). Methylnaltrexone, a quaternary derivative of the pure opioid antagonist naltrexone, has been reported to block undesired side effects of opioid pain medications predominantly mediated by peripherally located receptors, while sparing centrally mediated analgesic effect (Yuan, C.-S. et al., J. Pharm. Exp. Ther. 300:118-123 (2002)). It has been reported that methylnaltrexone does not cross the blood-brain barrier in humans (Foss, J. F., The American Journal of Surgery 182 (Suppl to November 2001):19S-26S (2001)).
There still exists a need in the art to provide efficient analgesia without CNS-mediated side effects.
The present invention is related to the discovery that N-alkyl substituted hydromorphones represented by Formula I act as xcexc opioid receptor agonists, and that they do not penetrate the central nervous system (CNS).
The invention is also related to treating, preventing or ameliorating pain, especially chronic pain, in a mammal in need thereof by administering an effective amount of a compound of Formula I as described herein.
The compounds useful in the present invention have not been heretofor reported. Thus, one aspect of the present invention is directed to the novel N-alkyl substituted hydromorphones of Formula I.
Another aspect of the present invention is directed to the novel compounds of Formula I as xcexc opioid receptor agonists.
Also, an aspect of the present invention is to provide a pharmaceutical composition useful for treating, preventing or ameliorating pain, containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.
Additional embodiments and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.